title: Oncogenic RAS directs silencing of tumor suppressor genes through ordered recruitment of transcriptional repressors.
abstract: We previously identified 28 cofactors through which a RAS oncoprotein directs transcriptional silencing of Fas and other tumor suppressor genes (TSGs). Here we performed RNAi-based epistasis experiments and found that RAS-directed silencing occurs through a highly ordered pathway that is initiated by binding of ZFP354B, a sequence-specific DNA-binding protein, and culminates in recruitment of the DNA methyltransferase DNMT1. RNAi and pharmacological inhibition experiments reveal that silencing requires continuous function of RAS and its cofactors and can be rapidly reversed, which may have therapeutic implications for reactivation of silenced TSGs in RAS-positive cancers.
authors.affiliation: Department of Pathology, Yale University School of Medicine, New Haven, Connecticut 06520, USA;
authors.forename: Narendra
authors.initials: N
authors.lastname: Wajapeyee
authors.forename: Sunil K
authors.initials: SK
authors.lastname: Malonia
authors.forename: Rajendra K
authors.initials: RK
authors.lastname: Palakurthy
authors.forename: Michael R
authors.initials: MR
authors.lastname: Green
mesh_terms: D000818:Animals; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D016147:Genes, Tumor Suppressor; D051379:Mice; D008954:Models, Biological; D041681:NIH 3T3 Cells; D011485:Protein Binding; D034622:RNA Interference; D015398:Signal Transduction; D019014:fas Receptor / Q000235:genetics / Q000378:metabolism; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: C491899:Fas protein, mouse; D019014:fas Receptor; D018631:ras Proteins
keywords: DNMT1; RAS; RNA interference; ZFP354B; epigenetic silencing; epistasis analysis